Interstate 20 (I-20) is the main east–west Interstate Highway in the state of South Carolina, linking the state with important transportation and business hubs to the north, west, and south, including Atlanta, Georgia; Charlotte, North Carolina ; Savannah, Georgia ; and Washington, D.C.. I-20 travels 141.51 miles (227.74 km) west to east, from the Georgia state line at North Augusta, through Columbia, to end at I-95 in Florence. Past I-95, the roadway continues as Interstate 20 Business for about two miles (3.2 km) to U.S. Route 76 (US 76), which goes to downtown Florence.

U.S. Route 601 (US 601) is a north–south United States highway that runs for 316.3 miles (509.0 km) from U.S. Route 321, near Tarboro, South Carolina, to U.S. Route 52, in Mount Airy, North Carolina. In North Carolina, it is one of the main north-south corridors connecting the cities of Salisbury, Mocksville, and Mount Airy.